2-0,0-dithiophosphoryl-methyl-benzoxazole

ABSTRACT

2-O,O-DIETHYL-DITHIOPHOSPHORYL-METHYL-5,7-DICHLOROBENZOXAZOLE is disclosed as having insecticidal, acaricidal and fungicidal activity.

I United States Patent [151 3,674,803 Scherer et al. July 4, 1972 [54]2-0,0-DITHIOPHOSPHORYL-METHYL- BENZOXAZOLE [52] U.S.Cl. ..260/307D,424/272 [51] lnLCl. ..C07d 85/48 I lnvemorsl Seller", BadSoden/Taunus; Germ"! 581 Field oi Search ..260/307 D Stahler,Frankfurt/Main, both of Germany [73] Assignee: Farbwerke HoechstAktiengesellschafl vor- [56] Re'erences Cited mals Meister Lucius 81Bllllllllg, Frankfurt/Main,Gennany Filed: y 16,1969 2,877,155 3/1959Menvler ..167/33 21 APPLNQ; 342 04 Primary Examiner-AlexMazel AssistantExaminer-R. V. Rush Related U.S. Application Data Attorney-Curtis,Morris & Safford [63] Continuation-impart of Ser. No. 552,408, May 24,[57] ABSTRACT I966, abandoned.

2-0,0-DlETHYL-DITHIOPHOSPHORYL-METHYL-S,7- [30] F i A n i P i i D mDICHLOROBENZOXAZOLE is disclosed as having insec- Junc 9, I965 June 9,I965 ticidal, acaricidal and fungicidal activity.

1 Claim, No Drawings 1 2-0,0-DITHIOPHOSPHORYL-METHYLBENZOXAZOLE Thisapplication is a continuation-in-part application of our copendingapplication Ser. No. 552,408 filed May 24, 1966, now abandoned.

The present invention relates to a novel phosphoric acid ester, to itsmanufacture and use as an agent for combating noxious organisms.

The present invention provides processes for the manufacture of a novelphosphoric acid ester of Formula [II by reacting salts ofQo-diethyl-dithiophosphoric acid of Fom'iula l with dichlorobenzoxazolesof Formula II according to the folin which B represents an alkali metal,alkaline earth metal or ammonium cation or a cation of an organic base,and Y stands for a halogen atom or a reactive acid radical, for examplea sulfonic acid radical.

The novel compound has utility as a pesticide.

ZJ-laIogen-methyl-benzoxazoles of Formula II and sulfonic acid esters ofcorresponding 2-hydroxymethyl-benzoxazole were unknown up to now. Thepresent invention also relates to these novel compounds which may beprepared as follows:

72 grams of 2-chloroacetamino-4,6-dichlorophenol are heated for 30minutes with 0.5 gram of zinc chloride in 500 milliliters ofo-dichlorobenzene under such conditions that odichlorobenzene evaporatesslowly and until water does no longer pass with the o-dichlorobenzene.The reaction mixture is cooled to room temperature. The solution isshaken with water and the two layers are separated. The dichlorobenzeneis removed from the organic solution by distillation under reducedpressure. The residue which solidifies at about 40 C is recrystallizedfrom methanol. 58 grams of 2-chloromethyl-5,7-dichlorobenzoxazole havinga melting point of 63 to 64 C are obtained. Using this compound, apesticidal agent is prepared as indicated in Example 1.

In order to obtain pesticidal'compositions, the phosphoric acid ester ofFormula 111 may be mixed with inert solid or liquid carrier materials,with adhesives, wetting agents, and dispersing agents to be used aswettable powders, emulsions, or dusting powders. Such compositions mayalso be combined with other insecticides, or fungicides. Thecompositions are used in form of such preparations as to permit acontrol of the noxious organisms without causing injuries to the hostanimals, for example in the control of ectoparasites, or to the hostplants, for example in the control of phytopathogenic fungi.

As inert carrier materials, there may be used mineral substances forexample, aluminium silicates, alumina, kaolin, kieselguhr, or hydratedsilicic'acids. As inert carrier materials for liquid preparations theremay be used all usual and suitable inert organic solvents, for example,toluene, xylene, or other higher boiling aromatic compounds, diacetonealcohol, cyclohexanone, isophorone, gasolines, paraffin oils, dioxane,dimethyl formamide, dimethyl sulphoxide, ethyl acetate, butyl acetate,tetrahydrofurane and chlorobenzene.

As adhesives, there may be used glutinous cellulose products orpolyvinyl alcohols.

As wetting agents, there may be used all suitable emulsifiers, forexample, hydroxy-ethylated alkylphenols, salts of arylor alkyl-arylsulphonic acids, salts of methyl-taurine, salts of phenylcogasinesulphonic acids or soaps.

As dispersing agents there may be used salts of dried cellulose sulphiteliquors, e.g. potassium ligninsulphonate, salts of naphthalene-sulphonicacid and, if required, hydrated silicic acids or even kieselguhr.

insecticidal compositions obtained according to the invention maypreferably be used in the form of an emulsion concentrate containingfrom 10 to percent by weight of the compound of Formula II] and from 5to 20 percent by weight of a wetting agent, whereas the rest making uppercent by weight, is a suitable organic solvent.

When comparing 2-0,0-diethyl-dithiophosphoryl-methyl-5,7-dichlorobenzoxazole with2-0,0-diethyl-dithiophosphorylmethylbenzoxazole unsubstituted in thebenzene nucleus as known from U.S. Pat. No. 2,877,155, the novelcompound is advantageous in having a higher efficacy to pests as well asa lower toxicity for warm blooded animals as shown by the LD,

values for rats. These properties enable it to be used for controllingdomestic and storage pests as well as other troublesome organisms andectoparasites.

Moreover, the novel compound shows a good fungicidal effect in additionto the insecticidal and acaricidal effects, especially with mildew.

The following table illustrates the lower toxicity to warm bloodedanimals of the claimed compound in comparison with the known compoundmentioned above.

Effective ingredient LD (rat)2-0,0-diethyl-dithiophosphoryl-methylbenzoxazole (known compound) 30mg/kg rat 2-0,0diethyl-dithiophosphoryl-methyl-S,

7-dichlorobenzoxazole (according to inmg/kg rat vention) The followingexamples serve to illustrate the invention but they are not intended tolimit it thereto. The percentages are given by weight.

EXAMPLE 1 45 grams of the potassium salt of 0,0-diethyldithiophosphoricacid and 48 grams of 2-chloromethyl-5,7- dichlorobenzoxazole having amelting point of 63 to 64 C were refluxed for 15 minutes in millilitersof ethanol. The reaction mixture was cooled to room temperature and theprecipitated potassium chloride was filtered off. The ethanol wasremoved from the filtrate by distillation. 66 grams of 2-0,0-diethyldithiophosphoryl-methyl-5,7-dichlorobenzoxazole were left asa brown oil which after sometime solidified at 23 to 24 C.

Analysis: Found Calculated 7.9% P 8.2% p 18.6% C1 18.9% Cl EXAMPLE 2 Awettable powder is prepared from 45 percent of 2-0,'0diethyl-dithiophosphoryl-methyl-5 ,7-

dichlorobenzoxazole 42 percent of highly dispersed silicic acid 10percent of calcium salt of ligninsulfonic acid 1 percent of sodium saltof oleylmethyltauride 2 percent of partially saponified polyvinylacetate 70/8 8 (i.e. degree of polymerization 70; saponification number88 EXAMPLE 3 An emulsifiable concentrate is prepared from 70 percent of2-0,0-diethyl-dithiophosphoryl-methyl- 5,7-

dichlorobenzoxazole 10 percent of fatty acid polyglycol ester 6 percentof calcium salt of phenyl-sulfonic acid 14 percent of xylene (onlinucdEXAMPLE 4 Conccn- Destruc- Fattening pigs infested with lice(Haematopinus suis) were Active ingredient pcr ri r i f, each sprayedwith 0.8 to 1 liter of an aqueous emulsion containing 0.05 to 0.75percent of active ingredient which was 5 0'002 60 prepared from thefollowing formulation: I l

10 percent of 2-0,0-diethyl-dithiophosphoryl-methyl-5,7-

dichlorobenzoxazole (cfmmemial) 78 percent of ethanol 0 003 70 10percent of an alkylphenyl polyglycol ester 10 2 percent ofepichlorohydrin. All lice were killed. f R I EXAMPLE 5 (commercial) Thefollowing table illustrates some of the advantages of the (1H3 rm mclaimed compound in a formulation analogeous to that of the N C mpreceding example over known compounds as regards their i I effect onlarvae of Mexican bean beetles (Epilachna (czmomifo V varivestis): CH;

(commercial) tats; ia; EXAM,P,LE6 Active ingredient percent percent Inorder to establish the fungicidal effect of the compounds N 0. 001 90according to the invention, cultured plants were treated, five C1 0.002100 days after having been infested with fungi, with an aqueous(C2H5O)ZP S CHQ O suspension prepared from a wettable powder of thefollowing ll composition: 8 10 percent of2-0,0-diethyl-dithiophosphoryl-methyl-5,7-

dichlorobenzoxazole 20 percent of amorphous preparation of silicic acid(according to invention) 5 6.5 percent of sodium sulfate N 002 40 10percent of calcium lignin sulfonate 2 percent of alkylphenyl polyglycolester 1 2 1.5 percent of stearyl alcohol g The following table shows thesuperiority of the compound 0 according to the invention over the known2-0,0-diethyl- (known from U.S. Pat. No. 2, 877, 155)dithiophosphoryl-methyl-benzoxazole and the commercial 5- arninol-bis(dimethyl-amidophosphoryl )-3-phenyll ,2,4- triazole.

TABLE I Diminution of Conccntrainfestation Toxicity tion of about 2weeks to warm spray liquor after treatment blooded containing comparedwith animals, 10% of active untreated speci- LDw in ingredient, menPhaseolis nig,/kg. of percent spec,, percent rat C1 czHi 2 scHic I I(according to invention) N 0. 012 0. 025 30 @mong-s-cm-o I S n (knowncompound) IIIII2 0. 025 an 10-20 l( a)2N] PNC N N P ll (commcrcinl) soIf? 2-0,0-diethyl iithiophosphoryl-methyl-S,7-dichlorobenzoxazoleaccording to the invention was examined for its toxicity to warm-bloodedanimals in comparison with 2-0,0diethyldithiophosphoryl-methyl-benzoxazole as known from US. Pat. No.2,877,155 Example 11, and Claim 3.

The toxicity of said compounds was determined as LD according to themethod of Karber. This method has repeatedly curve in the coordinatesystem does not give a clear picture.

By the mathematical method developed by Karber the said variations arelimited to a minimum so that the LD, is rather exactly indicated.

The calculation is carried out according to the following generalformula 7 LD, Dm S/m in which Dm is the minimum dose to which allanimals react (i.e. by which they are killed),

S is the sum total of all (d. z)-values, and

z is half the sum of positively reacting (killed) animals of two groupsof animals succeeding one another with respect to dose, 1

dis the difference between two successive doses,

m is the number of animals per dose or the number 0 animals n srp p stsstflmam. m.

a. Determination of LB peroral, using stomach tube: The peroral acutetoxicity was tested using2-0,0diethyldithiophosphoryl-methylmS,7-dichloro-benzoxazole accordingto the invention and 2-0,0-diethyl-dithiophosphoryl-methylbenzoxazole.Each of the compounds was applied in the form of emulsifiable solutionsof the following composition, the percentages given by weight:

30 percent of active ingredient 50 percent of isophoron 8 percent ofxylene 12 percent of emulsifiers consisting of a mixture of calcium saltof tetrapropylene-benzene-sulfonic acid and polyglycol ester ofunsaturated fatty acids.

The test animals used were, in all tests, male rats being specificallypathogen-free, strain Wistar, body weight from 100 to 150 grams. Theanimals were kept over the test period in cages placed inair-conditioned rooms having a temperature of 21 C. The rats were fed ona material manufacture by Messrs. Altromin Gmbl-l. of Lage/Lippe,Germany, which is called Standard Atromin R, as well as on tap water adlibitum.

First, a preliminary, toxicity test was carried out to determine theapproximate limits of the toxicity range. Then, the preparations wereadministered per os, using a stomach tube, to groups of rats which hadbeen fed, each in a single but increasing dose calculated on mg ofactive substance per kg of body weight. The preparations fed were in theform of aqueous emulsions containing 0.25 and 0.1 percent of activeingredient respectively. The observation period after administration was7 days.

The animals died with convulsive tremors (phosphoric acid esterpoisoning) within 45 minutes to 24 hours after administration.

The autopsy of the killed animals did macroscopically not show anystriking finding, i.e. death was not caused by any mechanical action.

To a control group of 10 rats carrier material (i.e. preparation withoutactive ingredient) was administered per os, using a stomach tube, at thesame dosage as administered with the active preparation to kill all therats. Over the observation V period of 7 days post application, none ofthese rats showed almft liemsuivifidthehesti rhe resultsare given inTable II.

TABLE II 5 Active ingredient according to invention:

2-0,0-diethyl-dithiophosphoryl-methyl-S,7-dichlorobenzoxazoleDetermination of LD peroral, using stomach tube, on male rats beingspecifically pathogen-free, strain Wistar, body weight from to 150grams.

Dose of Active Ingredient Number of animals killed/ in mg/kg Number ofanimals tested d z s Body weight 200 10/10 75 9.5==7l2.5 125 9/10 455=225 80 1/10 30 0.5=l5 50 0/ 10 s=952 5 32 0/10 (remained unconsidered)Hence LD is 200(952.5/10)=104.75 Thus, LD, peroral using stomach tube ismglkg of rat.

Compound known from U.S. Pat. No. 2,877,155:

2-0,0-diethyl-dithiophosphoryl-methyl-benzoxazole. Determination of LD,peroral as given above.

Hence LD 55 (252.5/ 10) 29.75 Thus, LD peroral, using a stomach tube, is30 mg/kg of rat.

b. Determination of dermal LD The material used was as given sub (a).

First, a preliminary toxicity test was carried out to determine theapproximate limits of the toxicity range. Then, the preparations wereapplied by means of a brush to the shaven back skin of groups of 10 ratsthat had been fed normally. Each preparation was applied at an singlebut increasing dosage, calculated on mg of active ingredient per kg ofbody weight. For this purpose, the rats were stretched in a vice andclosely shaved from neck to tail over an area of from 1 to 1.5

cm right and left their spines by means of a specific shaving machine.The preparations were applied dermally to the whole area shaven in theform of aqueous emulsions containing 0.25 and 0.1 percent of activeingredient (without loss of preparation). Until the skin had completelydried the rats remained separately fixed for about 3 hours in order toprevent the preparation to be stripped or licked ofi the skin.Subsequently, each animal was separately placed in a cage. Theobservation period after application was 7 days.

The animals died with convulsive tremors (phosphoric acid esterpoisoning) within 4 to 48 hours after application. The autopsy of thekilled animals did macroscopically not show any striking finding.

To a control group of 10 rats carrier material (i.e. preparation withoutactive ingredient) was applied in the same manner as described above atthe same dosage as applied with active ingredient to kill all the rats.Over the observation period of 7 days post application, none of the ratsshowed any clinically detectable difference from normal behavior and allof them survived the test. The results are given in Table 111.

TABLE 111 Active ingredients according to invention:

2-0,0-diethyl-dithiophosphoryl-methyl-5,7-dichlorobenzoxazoleDetermination of LD dermal on male rats being specificallypathogen-free, strain Wistar, body weight from 100 to 150 grams.

Hence LD,, is 1750 (6450/10) 1105 Thus, LD dermal is l 105 mg/kg of rat.

Compound known from U.S. Pat. No. 2,877,155:

2-0,0-diethyl-dithiophosphoryl-methyl-benzoxazole. Determination of LDdermal as given above.

Dose of Active Ingredient Number of Animals Killed/ d in mg/kg Number ofAnimals Tested Body Weight 1000 /10 (remained unconsidered) 500 10/10(remained unconsidered) 250 10/10 (remained unconsidered) 200 10/10 5095475 150 9/10 25-9 225 125 9/10 25 8.5 212.5 100 8/10 257 175 Hence LD is200 (l287.5/l0) 71.25 Thus, the dermal LD is 71 mg/kg of rat.

EXAMPLE 8 2-0,0-diethyl-dithiophosphoryl-methyl-S,7-dichlorobenzoxazolewas tested and compared under the same test conditions with2-0,0-diethyl-dithiophosphorylmethylbenzoxazole not substituted bychlorine as known from U.S. Pat. No. 2,877,155 to determine theirinsecticidal and acaricidal effects. The test arrangement chosen waspartially so that the effect of the individual compositions could becompared over short and prolonged periods of time.

For carrying out the following Tests 1 and 2, compositions in the formof emulsifiable solutions containing the following components wereprepared, the percentages being by weight:

10 per cent active ingredient 78 per cent absolute ethyl alcohol 2 percent epichlorohydrin 10 per cent oethylated alkyl phenol with 10 mols ofethylene oxide For Test 3, the phosphoric acid esters mentioned weredissolved in acetone in a manner disclosed hereinafter.

TEST 1 Guinea pigs having a body weight of from 600 to 700 grams werebathed for half a minute in luke-warm emulsions each containing one ofthe active ingredients. The emulsions had been prepared using theabove-mentioned emulsifiable 10 percent solutions of these activeingredients. These solutions had been processed with water intoemulsions each containing an active ingredient in a concentration of 0.1or 0.05 percent. One guinea pig was used per composition andconcentration. One guinea pig that had been bathed in pure water servedas a control. After bathing, the guinea pigs were kept separately inwire-meshed cages at a temperature of 20-22 C. After the furs had dried(day zero) as well as after 1, 4, 6, 10, 13, 15, 18 and 25 days, partsof the guinea pigs's furs were cut, about 1 gram of hair per guinea pig.The hair of each guinea pig was equally spread on a petri dish and then10 ticks (Ornil/wdorus moubata, fifth nymphal stage) were placed on eachdish. The dishes were subsequently stored in an incubator at atemperature of 36 C. At intervals each of 3 days the mortality of theticks was determined. After 25 days a pronounced decrease in activitycould be established; for this reason the time for which the ticksstayed in the hair was prolonged from 3 to 5 days in order to obtainsignificant results.

The test results in Table IV show that the effect of the known substancein the hair of the test animals is still the same after 4 days as thatof the substance of the invention: all ticks are killed within 3 days.After a stay of 6 days and more in the incubator at 36 C, the effect ofthe known substance in the hair of the test animals is strongly reduced,whereas the compound of the invention preserves its full activity for 12more days.

TEST 2 Ticks (Omithodorus moubata) of the third nymphal stage werespray-treated in petri dishes with emulsions that had been prepared fromthe above-mentioned emulsifiable 10 percent solutions by dilution withwater. The content of active ingredient amounted to 0.05, 0.025, 0.012and 0.006 per cent respectively. For each spray-treatment 2 millilitersof emulsion were used which corresponded to an amount of activeingredient of 0.4 mg. 0.2 mg. 0.096 mg and 0.048 mg each per cm of thespray treated substrate.

10 ticks were used for each composition and concentration. After thetreatment the ticks were transferred to untreated petri dishes whichwere placed on a heating plate at 35 C. The morality of the ticks wasdetermined on the first, second and third day after treatment.

The test results indicated in Table V distinctly demonstrate that2-0,0-diethyl-dithiophosphoryl-methyl-5 ,7- dichlorobenzoxazole of theinvention has a substantial better and quicker efiect on ticks than theknown benzoxazole phosphoric acid ester not substituted by chlorine.

A repetition of this test carried out with two differently developedstages of ticks (Ornithodarus moubata, third and fifth nymphal stages)and partially modified concentrations of active ingredient confirmed theresults obtained in the first test as indicated in Table VI.

TEST 3 Solutions of 2-0,0-diethyl-dithiophosphoryl-methyl-5,7-dichlorobenzoxazole according to the invention and of 2-0,0-diethyl-dithiophosphoryl-methyl-benzoxazole as known from U.S. Pat. No.2,877,155 respectively in acetone were prepared in concentrations of0.025 and 0.012 percent of each compound. One milliliter each of thesesolutions was applied to the petri dishes having a diameter of 9 cm, andevenly distributed by waiving the dishes. After evaporation of thesolvent, the petri dishes being covered each with 0.373 mg of the activeingredient concerned per 100 cm, or with 0.186 mg of the activeingredient concerned per 100 cm of area, were stored unprotected at +50C in an incubator. At intervals of l, 2, 3 and 4 days, house flies(Musca domestica) were placed on each petri dish containing each activeingredient in both concentrations, and upon placing them in thelaboratory at +22C the effect of the residues was determined after 3hours.

For comparisons sake flies were placed immediately after evaporation ofthe solvent on petri dishes that had not been stored previously in theincubator. Untreated petri dishes served for a control.

The results of this test as indicated in Table VH show that the peuidishes treated with the phosphoric acid ester of 5,7-

. dichlorosubstituted benzoxazole exhibit a better insecticidal effectthan petri dishes that has been treated with the known compound that hadnot been substituted by chlorine. Hence, the conclusion can be drawnthat the compound substituted by chlorine in 5,7-position according tothe invention is effective against insects for a substantially longertime than the known compound that is not substituted by chlorine.

TABLE IV Concentration of active Mortality of ticks in percent aftercontacting hair which was cut days after bathing ingredients guinea pigsin emulsion in percent 0 day 1 day 4 days 6 days 11 days 13 days 15 days18 days days Emulsion containing:

5,7-dichloro compound according to 0.1 100 100 100 100 100 100 100 100100 invention 0. 05 100 100 100 100 100 100 100 100 100 Unsubstitutedcompound known from 0.1 100 100 100 100 100 100 100 80 20 U.S. Patent2,877,155 0.05 100 100 100 80 80 80 40 0 Control 0 0 0 0 0 0 0 0 n 0N0'1'E.-Eflects of active ingredients in hair of guinea pigs on ticks(Ornilhodorus moubata), 10 ticks per dosage.

TABLE v Concentration of active ingredient Mortality of ticks in percentNo'rE.Treatment of ticks (Omithodoruapzoubata), 10 ticks per dosage 3dnymphale stage.

TABLE VI Concentration of active ingredient Percent Milligram Mortalityof ticks in percent 3d nymphal stagedays after treatment 5th nymphalstagedays 7 after treatment in per 100 emulsion cm) 1 day 2 days 3 days1 day 2 days 3 days Emulsion containing:

5,7-dich1oro compound according to in- 0. 025 0. 2 70 100 0 80 80vention 0. 006 0. 048 40 80 0 0 Unsubstitnted compound known from 0. 0250. 2 30 60 60 0 50 50 US. Pat. 2,877,155 (1006 0. 048 0 10 10 0 0 20Control 0 0 0 0 0 o o 0 N0'm.-Treatment of ticks (Ornithodorus mouboln),10 ticks per dosage. Repetition' 3d nymphal stage and 5th nymphal stage.

TAiiLE vn Concentration of active Mortality of flies in percent after 3hours stay in compound Petri dishes stored before at Percent inMilligram 22C. 50C.

acetone per Active compound 100 cm! 0 day 1 day 2 days 3 days 4 days5,7-dichloro compound according to 0 025 0. 373 100 100 100 invention0.012 0 186 100 50 40 70 30 Unsubstituted compound known O. 025 0. 373100 50 10 10 0 from U.S. Pat. 2,877,155 0.012 0.186 100 10 0 0 0 Control0 0 0 0 0 0 0 Norm-Emacs of residues of active compounds on house flies(Musca domestica) after storage in Petri dishes at 50 0.; 10 film perdosage.

We claim: 11. 2-0,0-Diethyl-dithiophosphoryl-methyl-5,7-

5 dichlorobenzoxazole.

